Enhanced Egg-Induced Immunopathology Correlates With High IFN-γ in Murine Schistosomiasis: Identification of Two Epistatic Genetic Intervals

Abstract

The genetic basis of dissimilar immunopathology development among mouse strains infected with Schistosoma mansoni is not known. We performed a multipoint parametric linkage analysis on a cohort of F2 mice, offspring of brother-sister mating between (high pathology CBA × low pathology BL/6)F1 mice, to examine whether the observed differences in the type of immune response or the extent of hepatic immunopathology are linked to any particular genomic intervals. The F2 mice exhibited cytokine responses and immunopathologies that revealed a statistically significant correlation between prominent egg Ag-stimulated IFN-γ production by mesenteric lymph node cells and hepatic egg granuloma size. Increased IFN-γ production showed suggestive linkage to a dominant CBA locus on chromosome 1 and a recessive CBA locus on chromosome 5; significantly, there was an epistatic interaction between the two IFN-γ loci. An additional locus with suggestive linkage to granuloma formation and a CBA-recessive mode of inheritance was mapped to centromeric chromosome 13. Our analysis identified the first three genetic regions that appear to influence the immunopathology in murine schistosomiasis; however, further congenic dissection studies will furnish a more precise understanding of the genetic control of this disease.

Triggering and modulation of the host-parasite interplay byEchinococcus multilocularis: a review

“…In particular, the recent discovery of the IL-17 cytokine family has added a new dimension to the balance of inflammation and tolerance during parasite infections. The presence of IL-17-secreting CD4+ T (Th17) lymphocytes correlates with high hepatic pathology in murine schistosomiasis (Rutitzky et al 2005), which prompts a more detailed similar investigation in murine AE. Another member of the IL-17 cytokine family, IL-25 (or IL-17E), also has an important role in parasitic infections.…”

Identifying phenotypes involved in susceptibility to Schistosoma mansoni infection in F1B6CBA mice

“…Thus, mouse experimental crosses have been a suitable strategy for mapping genes involved in different complex diseases including the immune response against S. mansoni (Rutitzky et al 2005;Smith et al 2009). Several studies report differences in the hepatic fibrosis or granuloma size in different inbreed mouse lines *Corresponding author: luispmoro@usal.es Luis Pérez del Villar et al 530 (Cheever 1986;Cheever et al 1983;Cheever et al 2002).…”

CD4 T cells producing pro-inflammatory interleukin-17 mediate high pathology in schistosomiasis

“…Human patient populations infected with this parasite display a great variation in the magnitude of clinical disease. Likewise, in the murine model, the CBA and C3H strains typically develop a more pronounced hepatic immunopathology characterized by larger egg granulomas with hepatic parenchymal inflammation, whereas in C57BL/6 (BL/6) mice the lesions are uniformly less severe (Cheever et al 1987, Rutitzky et al 2005a. Several independent lines of evidence have linked the high pathology to the persistence of a net pro-inflammatory state marked by the increase of Th1-type cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, the deficiency of anti-inflammatory Th2-type cytokines such as interleukin (IL)-4 and IL-10, or both.…”

“…Several independent lines of evidence have linked the high pathology to the persistence of a net pro-inflammatory state marked by the increase of Th1-type cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, the deficiency of anti-inflammatory Th2-type cytokines such as interleukin (IL)-4 and IL-10, or both. For example, schistosome egg antigen (SEA)-stimulated mesenteric lymph node cells from 7 week-infected high pathology CBA mice produce significant amounts of IFN-γ, whereas those from low pathology BL/ 6 mice do not (Rutitzky et al 2001(Rutitzky et al , 2003a(Rutitzky et al , 2005a. Moreover, mice with impaired costimulatory B7-CD28 (King et al 1996, Hernandez et al 1999 (Rutitzky et al 2003b) systems, or deficient in anti-inflammatory cytokines IL-4 (Brunet et al 1997) and IL-10 (Hoffmann et al 2000, Sadler et al 2003, or in B cells (Hernandez et al 1997) or in alternatively activated macrophages (Herbert et al 2004), display a pro-inflammatory cytokine dominance and are prone to pathology exacerbation.…”